U.S. patent number 9,913,976 [Application Number 13/162,047] was granted by the patent office on 2018-03-13 for systems and methods for stimulating and monitoring biological tissue.
This patent grant is currently assigned to Highland Instruments, Inc.. The grantee listed for this patent is Uri Tzvi Eden, Timothy Andrew Wagner. Invention is credited to Uri Tzvi Eden, Timothy Andrew Wagner.
United States Patent |
9,913,976 |
Wagner , et al. |
March 13, 2018 |
Systems and methods for stimulating and monitoring biological
tissue
Abstract
The invention generally relates to apparatuses and methods for
stimulating and monitoring biological tissue. In certain aspects,
the invention provides a system for stimulating and monitoring
tissue, the system including a first energy source, a second energy
source, and an imaging device, in which the system is configured
such that the first and second energy sources target the same
region of tissue and the combined effect of the first and second
energy sources stimulates the region of tissue.
Inventors: |
Wagner; Timothy Andrew
(Cambridge, MA), Eden; Uri Tzvi (Somerville, MA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Wagner; Timothy Andrew
Eden; Uri Tzvi |
Cambridge
Somerville |
MA
MA |
US
US |
|
|
Assignee: |
Highland Instruments, Inc.
(Cambridge, MA)
|
Family
ID: |
44902392 |
Appl.
No.: |
13/162,047 |
Filed: |
June 16, 2011 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20110275927 A1 |
Nov 10, 2011 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N
1/36017 (20130101); A61N 1/20 (20130101); A61N
1/40 (20130101); A61N 1/32 (20130101); A61N
1/36182 (20130101); A61N 1/36071 (20130101); A61N
2007/0026 (20130101); A61B 6/506 (20130101); A61N
1/36025 (20130101); A61N 1/36096 (20130101); A61N
1/36082 (20130101); A61N 1/0529 (20130101) |
Current International
Class: |
A61N
1/36 (20060101); A61N 7/00 (20060101); A61N
1/32 (20060101); A61N 1/20 (20060101); A61N
1/40 (20060101); A61N 1/05 (20060101); A61B
6/00 (20060101); A61N 1/362 (20060101) |
Field of
Search: |
;607/2-3,45 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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2007/149811 |
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Dec 2007 |
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WO |
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2010/009141 |
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Jan 2010 |
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WO |
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2010/017392 |
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Feb 2010 |
|
WO |
|
2012/101093 |
|
Aug 2012 |
|
WO |
|
2013/054257 |
|
Apr 2013 |
|
WO |
|
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|
Primary Examiner: Bockelman; Mark W
Attorney, Agent or Firm: Brown Rudnick LLP
Claims
What is claimed is:
1. A system for stimulating and monitoring tissue, the system
comprising: a first non-invasive energy source that emits an
electric field; a second non-invasive energy source that emits a
mechanical field; an imaging device; and a controller comprising
one or more programs that are configured to tune stimulation by
identifying tissue distribution data of a subject from imaging data
received from the imaging device, determining tissue boundaries in
a stimulation area from the tissue distribution data, constructing
a computational mesh that captures tissue segmentation demonstrated
in the imaging data and accounts for tissue distribution and tissue
boundaries, and calculating altered tissue mechanical properties in
the stimulation area relative to the electrical field to be applied
in the stimulation area, wherein the controller outputs a dose to
be provided by the first and/or second non-invasive energy
sources.
2. The system according to claim 1, wherein the imaging device is
selected from the group consisting of: a magnetic resonance imaging
device, a functional magnetic resonance imaging device, a device
for performing a CT scan, and a device for performing
electroencephalography.
3. The system according to claim 1, wherein the imaging device
provides feedback to an operator as to the effect of the first and
second energy sources on the tissue.
4. The system according to claim 1, wherein the second energy
source is an ultrasound device.
5. The system according to claim 1, wherein the electric field is
pulsed.
6. The system according to claim 1, wherein the electric field is
time varying.
7. The system according to claim 1, wherein the electric field is
pulsed a plurality of times, and each pulse may be for a different
length of time.
8. The system according to claim 1, wherein the electric field is
time invariant.
9. The system according to claim 1, wherein the mechanical field is
pulsed.
10. The system according to claim 1, wherein the mechanical field
is time varying.
11. The system according to claim 1, wherein the mechanical field
is pulsed a plurality of times, and each pulse may be for a
different length of time.
12. The system according to claim 1, wherein the electric field is
focused.
13. The system according to claim 1, wherein the mechanical field
is focused.
14. The system according to claim 1, wherein both the electric
field and the mechanical field are focused.
15. The system according to claim 1, wherein the first and second
energy sources are applied to a structure or multiple structures
within the brain or the nervous system selected from the group
consisting of: dorsal lateral prefrontal cortex, any component of
the basal ganglia, nucleus accumbens, gastric nuclei, brainstem,
thalamus, inferior colliculus, superior colliculus, periaqueductal
gray, primary motor cortex, supplementary motor cortex, occipital
lobe, Brodmann areas 1-48, primary sensory cortex, primary visual
cortex, primary auditory cortex, amygdala, hippocampus, cochlea,
cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal
lobe, parietal lobe, sub-cortical structures, and spinal cord.
16. The system according to claim 1, wherein the tissue is neural
tissue.
17. The system according to claim 16, wherein the effect of the
stimulation alters neural function past the duration of
stimulation.
Description
RELATED APPLICATIONS
The present application is a continuation-in-part of U.S.
nonprovisional application Ser. No. 11/764,468, filed Jun. 18,
2007, which claims the benefit of and priority to U.S. provisional
application Ser. No. 60/814,843, filed Jun. 19, 2006, the content
of each of which is incorporated by reference herein in its
entirety.
FIELD OF THE INVENTION
The invention generally relates to systems and methods for
stimulating and monitoring biological tissue.
BACKGROUND
Stimulation of tissue in humans and other animals is used in a
number of clinical applications as well as in clinical and general
biological research. In particular, stimulation of neural tissue
has been used in the treatment of various diseases including
Parkinson's disease, depression, and intractable pain. The
stimulation may be applied invasively, e.g., by performing surgery
to remove a portion of the skull and implanting electrodes in a
specific location within brain tissue, or non-invasively, e.g.,
transcranial direct current stimulation and transcranial magnetic
stimulation.
A problem with tissue stimulation is an inability to monitor an
effect of the stimulation on the tissue, particularly in real-time.
For example, non-invasive stimulation of brain tissue involves
stimulation of a large area of tissue that is generally not well
characterized and that can be significantly perturbed by natural or
pathological features of the brain tissue. The lack of monitoring
makes it difficult to effectively target (localize) the stimulation
to the desired region of tissue, dose the stimulation, and
characterize safety parameters.
SUMMARY
The invention provides systems and methods that integrate tissue
stimulation with monitoring of at least the stimulated tissue.
Systems and methods of the invention allow for implementation of a
closed loop system that allows for tuning of stimulation based on
real-time feedback that is gathered from a monitoring device, e.g.,
an imaging device. In this manner, the stimulation can be modified
to achieve a desired response relative to the information/feedback
that is gathered. Particularly, data generated from real-time
monitoring of the tissue that is stimulated can be used to modulate
the stimulation by aiding in the targeting (localizing) of
stimulation, dosing of stimulation, characterizing safety
parameters, analyzing the online and/or effects of stimulation,
and/or maximizing the therapeutic effect of stimulation.
In certain aspects, the invention provides systems for stimulating
and monitoring tissue. In certain embodiments, the systems include
a first energy source, a second energy source, and an imaging
device, in which the system is configured such that the first and
second energy sources target the same region of tissue and the
combined effect of the first and second energy sources stimulates
the region of tissue. Any imaging device known in the art may be
used with systems of the invention. Exemplary imaging devices
include a magnetic resonance imaging device, a functional magnetic
resonance imaging device, a device for performing a CT scan, and a
device for performing electroencephalography. In certain
embodiments, the imaging device provides feedback to an operator as
to the effect of the first and second energy sources on the
tissue.
Any energy sources known in the art may be used with systems of the
invention. In certain embodiments, the first energy source is an
electric source that produces an electric field. The electric filed
may be pulsed, time varying, pulsed a plurality of time with each
pulse being for a different length of time, or time invariant. In
certain embodiments, the second energy source is a source that
produces a mechanical field, such as an ultrasound device. The
mechanical filed may be pulsed, time varying, or pulsed a plurality
of time with each pulse being for a different length of time. In
certain embodiments, the electric field and/or the mechanical field
is focused.
The first and second energy sources may be applied to any tissue.
In certain embodiments, the first and second energy sources are
applied to a structure or multiple structures within the brain or
the nervous system such as the dorsal lateral prefrontal cortex,
any component of the basal ganglia, nucleus accumbens, gastric
nuclei, brainstem, thalamus, inferior colliculus, superior
colliculus, periaqueductal gray, primary motor cortex,
supplementary motor cortex, occipital lobe, Brodmann areas 1-48,
primary sensory cortex, primary visual cortex, primary auditory
cortex, amygdala, hippocampus, cochlea, cranial nerves, cerebellum,
frontal lobe, occipital lobe, temporal lobe, parietal lobe,
sub-cortical structures, and spinal cord. In particular
embodiments, the tissue is neural tissue, and the affect of the
stimulation alters neural function past the duration of
stimulation.
Another aspect of the invention provides methods for stimulating
and monitoring tissue. In certain embodiments, methods of the
invention involve applying a first type of energy to a region of
tissue, applying a second type of energy to the region of tissue,
the combined effect of the first and second energy sources
stimulates the region of tissue, and imaging at least the region of
tissue. The imaging may provide feedback as to the effect of the
first and second types of energy provided to the tissue. In certain
embodiments, applying and imaging occur simultaneously. In other
embodiments, applying and imaging occur sequentially.
BRIEF DESCRIPTION OF THE DRAWINGS
The above-mentioned and other features and objects of this
invention, and the manner of attaining them, will become more
apparent and the invention itself will be better understood by
reference to the following description of embodiments of the
invention taken in conjunction with the accompanying drawings,
wherein:
FIG. 1 is a plan view of one embodiment of an apparatus for
stimulating biological tissue constructed in accordance with the
principles of the present disclosure;
FIG. 2 is a top plan view of an exemplary embodiment of an
apparatus for stimulating biological tissue constructed in
accordance with the principles of the present disclosure;
FIG. 3 is a top plan view of an exemplary embodiment of an
apparatus for stimulating biological tissue implementing a chemical
source for altering permittivity constructed in accordance with the
principles of the present disclosure;
FIG. 4 is a top plan view of an exemplary embodiment of an
apparatus for stimulating biological tissue implementing a
radiation source for altering permittivity constructed in
accordance with the principles of the present disclosure; and
FIG. 5 is a top plan view of another exemplary embodiment of an
apparatus for stimulating biological tissue implementing an optical
beam for altering permittivity constructed in accordance with the
principles of the present disclosure.
DETAILED DESCRIPTION
It is envisioned that the present disclosure may be used to
stimulate biological tissue in-vivo comprising an electric source
that is placed on the body to generate an electric field and a
means for altering the permittivity of tissue relative to the
electric field, whereby the alteration of the tissue permittivity
relative to the electric field generates a displacement current in
the tissue. The exemplary embodiments of the apparatuses and
methods disclosed can be employed in the area of neural
stimulation, where amplified, focused, direction altered, and/or
attenuated currents could be used to alter neural activity via
directly stimulating neurons, depolarizing neurons, hyperpolarizing
neurons, modifying neural membrane potentials, altering the level
of neural cell excitability, and/or altering the likelihood of a
neural cell firing. Likewise, the method for stimulating biological
tissue may also be employed in the area of muscular stimulation,
including cardiac stimulation, where amplified, focused, direction
altered, and/or attenuated currents could be used to alter muscular
activity via direct stimulation, depolarizing muscle cells,
hyperpolarizing muscle cells, modifying membrane potentials,
altering the level of muscle cell excitability, and/or altering the
likelihood of cell firing. Similarly, it is envisioned that the
present disclosure may be employed in the area of cellular
metabolism, physical therapy, drug delivery, and gene therapy.
Detailed embodiments of the present disclosure are disclosed
herein, however, it is to be understood that the described
embodiments are merely exemplary of the disclosure, which may be
embodied in various forms. Therefore, specific functional details
disclosed herein are not to be interpreted as limiting, but merely
as a basis for the claims and as a representative basis for
teaching one skilled in the art to variously employ the present
disclosure in virtually any appropriately detailed embodiment.
The components of the tissue stimulation method according to the
present disclosure are fabricated from materials suitable for a
variety medical applications, such as, for example, polymerics,
gels, films, and/or metals, depending on the particular application
and/or preference. Semi-rigid and rigid polymerics are contemplated
for fabrication, as well as resilient materials, such as molded
medical grade polyurethane, as well as flexible or malleable
materials. The motors, gearing, electronics, power components,
electrodes, and transducers of the method may be fabricated from
those suitable for a variety of medical applications. The method
according to the present disclosure may also include circuit
boards, circuitry, processor components, etc. for computerized
control. One skilled in the art, however, will realize that other
materials and fabrication methods suitable for assembly and
manufacture, in accordance with the present disclosure, also would
be appropriate.
The following discussion includes a description of the components
and exemplary methods for generating currents in biological tissues
in accordance with the principles of the present disclosure.
Alternate embodiments are also disclosed. Reference will now be
made in detail to the exemplary embodiments of the present
disclosure illustrated in the accompanying figures wherein like
reference numerals indicate the similar parts throughout the
figures.
Turning now to FIG. 1, which illustrates an exemplary embodiment of
an apparatus 10 to alter currents, e.g., amplify, focus, alter
direction, and/or attenuate in the presence of an applied electric
field or applied current source by the combined application of a
mechanical field within a biological material to stimulate the
biological cells and/or tissue in accordance with the present
disclosure. For example, the apparatus 10 illustrated in FIG. 1
according to the present disclosure may be applied to the area of
neural stimulation. An initial source electric field 14 results in
a current in the tissue. The electric field 14 is created by an
electric source, current or voltage source. As described in further
detail below, the permittivity of the tissue is altered relative to
the electric field, for example by a mechanical field, thereby
generating an additional displacement current.
Electrodes 12 are applied to the scalp and generate a low magnitude
electric field 14 over a large brain region. While electrodes 12
are used and applied to the scalp in this exemplary embodiment, it
is envisioned that the electrodes may be applied to a number of
different areas on the body including areas around the scalp. It is
also envisioned that one electrode may be placed proximal to the
tissue being stimulated and the other distant, such as one
electrode on the scalp and one on the thorax. It is further
envisioned that electric source could be mono-polar with just a
single electrode, or multi-polar with multiple electrodes.
Similarly, the electric source may be applied to tissue via any
medically acceptable medium. It is also envisioned that means could
be used where the electric source does not need to be in direct
contact with the tissue, such as for example, inductive magnetic
sources where the entire tissue region is placed within a large
solenoid generating magnetic fields or near a coil generating
magnetic fields, where the magnetic fields induce electric currents
in the tissue.
The electric source may be direct current (DC) or alternating
current (AC) and may be applied inside or outside the tissue of
interest. Additionally, the source may be time varying. Similarly,
the source may be pulsed and may be comprised of time varying pulse
forms. The source may be an impulse. Also, the source according to
the present disclosure may be intermittent. The electric field
source could also work as a component in the imaging process.
A mechanical source such as an ultrasound source 16 is applied on
the scalp and provides concentrated acoustic energy 18, i.e.,
mechanical field to a focused region of neural tissue, affecting a
smaller number of neurons 22 than affected by the electric field
14, by the mechanical field 18 altering the tissue permittivity
relative to the applied electric field 14, and thereby generating
the altered current 20. The mechanical source may be any acoustic
source such as an ultrasound device. Generally, such device may be
a device composed of electromechanical transducers capable of
converting an electrical signal to mechanical energy such as those
containing piezoelectric materials, a device composed of
electromechanical transducers capable of converting an electrical
signal to mechanical energy such as those in an acoustic speaker
that implement electromagnets, a device in which the mechanical
source is coupled to a separate mechanical apparatus that drives
the system, or any similar device capable of converting chemical,
plasma, electrical, nuclear, or thermal energy to mechanical energy
and generating a mechanical field.
Furthermore, the mechanical field could be generated via an
ultrasound device, such as an ultrasound transducer that could be
used for imaging tissue. The mechanical field may be coupled to
tissue via a bridging medium, such as a container of saline to
assist in the focusing or through gels and/or pastes which alter
the acoustic impedance between the mechanical source and the
tissue. The mechanical field may be time varying, pulsed, an
impulse, or may be comprised of time varying pulse forms. It is
envisioned that the mechanical source may be applied inside or
outside of the tissue of interest. There are no limitations as to
the frequencies that can be applied via the mechanical source,
however, exemplary mechanical field frequencies range from the sub
kHZ to 1000s of MHz. Additionally, multiple transducers providing
multiple mechanical fields with similar or differing frequencies,
and/or similar or different mechanical field waveforms may be
used--such as in an array of sources like those used in focused
ultrasound arrays. Similarly, multiple varied electric fields could
also be applied. The combined fields, electric and mechanical, may
be controlled intermittently to cause specific patterns of spiking
activity or alterations in neural excitability. For example, the
device may produce a periodic signal at a fixed frequency, or high
frequency signals at a pulsed frequency to cause stimulation at
pulse frequencies shown to be effective in treating numerous
pathologies. Such stimulation waveforms may be those implemented in
rapid or theta burst TMS treatments, deep brain stimulation
treatments, epidural brain stimulation treatments, spinal cord
stimulation treatments, or for peripheral electrical stimulation
nerve treatments. The ultrasound source may be placed at any
location relative to the electrode locations, i.e., within, on top
of, below, or outside the same location as the electrodes as long
as components of the electric field and mechanical field are in the
same region. The locations of the sources should be relative to
each other such that the fields intersect relative to the tissue
and cells to be stimulated, or to direct the current alteration
relative to the cellular components being stimulated.
The apparatus and method according to the present disclosure
generates capacitive currents via permittivity alterations, which
can be significant in magnitude, especially in the presence of low
frequency applied electric fields. Tissue permittivities in
biological tissues are much higher than most other non biological
materials, especially for low frequency applied electric fields
where the penetration depths of electric fields are highest. This
is because the permittivity is inversely related to the frequency
of the applied electric field, such that the tissue permittivity
magnitude is higher with lower frequencies. For example, for
electric field frequencies below 100,000 Hz, brain tissue has
permittivity magnitudes as high as or greater than 10^8
(100,000,000) times the permittivity of free space (8.854*10^-12
farad per meter), and as such, minimal local perturbations of the
relative magnitude can lead to significant displacement current
generation. As the frequency of the electric field increases, the
relative permittivity decreases by orders of magnitude, dropping to
magnitudes of approximately 10^3 times the permittivity of free
space (8.854*10^-12 farad per meter) for electric field frequencies
of approximately 100,000 Hz. Additionally, by not being constrained
to higher electric field frequencies, the method according to the
present disclosure is an advantageous method for stimulating
biological tissue due to lowered penetration depth limitations and
thus lowered field strength requirements. Additionally, because
displacement currents are generated in the area of the permittivity
change, focusing can be accomplished via the ultrasound alone. For
example, to generate capacitive currents via a permittivity
perturbation relative to an applied electric field as described
above, broad DC or a low frequency electric source field well below
the cellular stimulation threshold is applied to a brain region but
stimulation effects are locally focused in a smaller region by
altering the tissue permittivity in the focused region of a
mechanical field generated by a mechanical source such as an
ultrasound source. This could be done noninvasively with the
electrodes and the ultrasound device both placed on the scalp
surface such that the fields penetrate the tissue surrounding the
brain region and intersect in the targeted brain location, or with
one or both of the electrodes and/or the ultrasound device
implanted below the scalp surface (in the brain or any of the
surrounding tissue) such that the fields intersect in the targeted
region.
A displacement current is generated by the modification of the
permittivity in the presence of the sub threshold electric field
and provides a stimulatory signal. In addition to the main
permittivity change that occurs in the tissues, which is
responsible for stimulation (i.e., the generation of the altered
currents for stimulation), a conductivity change could also occur
in the tissue, which secondarily alters the ohmic component of the
currents. In a further embodiment, the displacement current
generation and altered ohmic current components may combine for
stimulation. Generally, tissue conductivities vary slightly as a
function of the applied electric field frequency over the DC to
100,000 Hz frequency range, but not to the same degree as the
permittivities, and increase with the increasing frequency of the
applied electric field. Additionally in biological tissues, unlike
other materials, the conductivity and permittivity do not show a
simple one-to-one relationship as a function of the applied
electric field frequency. The permittivity ranges are as discussed
above.
Although the process described may be accomplished at any frequency
of the applied electric field, the method in an exemplary
embodiment is applied with lower frequency applied electric fields
due to the fact the permittivity magnitudes of tissues, as high as
or greater than 10^8 times the permittivity of free space, and the
electric field penetration depths are highest for low frequency
applied electric fields. Higher frequency applied electric fields
may be less desirable as they will require greater radiation power
to penetrate the tissue and/or a more pronounced mechanical source
for permittivity alteration to achieve the same relative tissue
permittivity change, i.e., at higher applied electric field
frequencies the permittivity of the tissue is lower and as such
would need a greater overall perturbation to have the same overall
change in permittivity of a tissue as at a lower frequency. Applied
electric field frequencies in the range of DC to approximately
100,000 Hz frequencies are advantageous due to the high tissue
permittivity in this frequency band and the high penetration depth
for biological tissues at these frequencies. In this band, tissues
are within the so called `alpha dispersion band` where relative
tissue permittivity magnitudes are maximally elevated (i.e., as
high as or greater than 10^8 times the permittivity of free space).
Frequencies above approximately 100,000 to 1,000,000 Hz for the
applied electric fields are still applicable for the method
described in generating displacement currents for the stimulation
of biologic cells and tissue, however, both the tissue permittivity
and penetration depth are limited for biological tissues in this
band compared to the previous band but displacement currents of
sufficient magnitude can still be generated for some applications.
In this range, the magnitude of the applied electric field will
likely need to be increased, or the method used to alter the
permittivity relative to the applied electric field increased to
bring about a greater permittivity change, relative to the tissue's
permittivity magnitude for the applied electric field frequency.
Additionally, due to potential safety concerns for some
applications, it may be necessary to limit the time of application
of the fields or to pulse the fields, as opposed to the continuous
application that is possible in the prior band. For tissues or
applications where the safety concerns preclude the technique in
deeper tissues, the technique could still be applied in more
superficial applications in a noninvasive manner or via an invasive
method. Higher frequency applied electric fields, above 1,000,000
to 100,000,000 Hz, could be used in generating displacement
currents for the stimulation of biologic cells and tissue. However,
this would require a more sufficient permittivity alteration or
electromagnetic radiation, and as such is less than ideal in terms
of safety than the earlier bands. For frequencies of the applied
electric field above 100,000,000 Hz, biologic cell and tissue
stimulation may still be possible, but may be limited for
specialized applications that require less significant displacement
currents.
The focus of the electric and mechanical fields to generate an
altered current according to the present disclosure may be directed
to various structures within the brain or nervous system including
but not limited to dorsal lateral prefrontal cortex, any component
of the basal ganglia, nucleus accumbens, gastric nuclei, brainstem,
thalamus, inferior colliculus, superior colliculus, periaqueductal
gray, primary motor cortex, supplementary motor cortex, occipital
lobe, Brodmann areas 1-48, primary sensory cortex, primary visual
cortex, primary auditory cortex, amygdala, hippocampus, cochlea,
cranial nerves, cerebellum, frontal lobe, occipital lobe, temporal
lobe, parietal lobe, sub-cortical structures, spinal cord, nerve
roots, sensory organs, and peripheral nerves.
The focused tissue may be selected such that a wide variety of
pathologies may be treated. Such pathologies that may be treated
include but are not limited to Multiple Sclerosis, Amyotrophic
Lateral Sclerosis, Alzheimer's Disease, Dystonia, Tics, Spinal Cord
Injury, Traumatic Brain Injury, Drug Craving, Food Craving, Alcohol
Craving, Nicotine Craving, Stuttering, Tinnitus, Spasticity,
Parkinson's Disease, Parkinsonianism, Obsessions, Depression,
Schizophrenia, Bipolar Disorder, Acute Mania, Catonia,
Post-Traumatic Stress Disorder, Autism, Chronic Pain Syndrome,
Phantom Limb Pain, Epilepsy, Stroke, Auditory Hallucinations,
Movement Disorders, Neurodegenerative Disorders, Pain Disorders,
Metabolic Disorders, Addictive Disorders, Psychiatric Disorders,
Traumatic Nerve Injury, and Sensory Disorders. Furthermore,
electric and mechanical fields to generate an altered current may
be focused on specific brain or neural structures to enact
procedures including sensory augmentation, sensory alteration,
anesthesia induction and maintenance, brain mapping, epileptic
mapping, neural atrophy reduction, neuroprosthetic interaction or
control with nervous system, stroke and traumatic injury
neurorehabilitation, bladder control, assisting breathing, cardiac
pacing, muscle stimulation, and treatment of pain syndromes, such
as those caused by migraine, neuropathies, and low-back pain; or
internal visceral diseases, such as chronic pancreatitis or cancer.
The methods herein could be expanded to any form of arthritis,
impingement disorders, overuse injuries, entrapment disorders,
and/or any muscle, skeletal, or connective tissue disorder which
leads to chronic pain, central sensitization of the pain signals,
and/or an inflammatory response.
In the focused region of tissue to which the mechanical fields are
delivered, the excitability of individual neurons can be heightened
to the point that the neurons can be stimulated by the combined
fields, or be affected such as to cause or amplify the alteration
of the neural excitability caused by the altered currents, either
through an increase or decrease in the excitability of the neurons.
This alteration of neural excitability can last past the duration
of stimulation and thus be used as a basis to provide lasting
treatment. Additionally, the combined fields can be provided in
multiple, but separate sessions to have a summed, or carry-over
effect, on the excitability of the cells and tissue. The combined
fields can be provided prior to another form of stimulation, to
prime the tissue making it more or less susceptible to alternate,
follow-up forms of stimulation. Furthermore, the combined fields
can be provided after an alternate form of stimulation, where the
alternate form of stimulation is used to prime the tissue to make
it more or less susceptible to the form of stimulation disclosed
herein. Furthermore, the combined fields could be applied for a
chronic period of time.
FIG. 2 illustrates a set up 30 to perform a method for generating
an altered current with a newly generated displacement current 32
for stimulation in biologic tissue 34 through the combined effects
of an electric field 36 and a mechanical field 38. A tissue or
composite of tissues 34 is placed adjacent to the anode and cathode
of an electric source 40 which generates an electric field 36. The
electric field 36 is combined with a mechanical, e.g., ultrasound
field 38 which can be focused on the tissue 34 and generated via an
ultrasound transducer 42. In a sub-region of tissue 44 where the
mechanical field 38 is focused and intersects with the electric
field 36, a displacement current 32 is generated. By vibrating
and/or mechanically perturbing the sub-region of tissue 44, the
permittivity of the tissue 44 can be altered relative to the
applied electric field 36 to generate a displacement current 32 in
addition to the current that would be present due to the source
electric field 36 and altered due to conductivity changes in the
tissue caused by the mechanical perturbation.
By providing the mechanical field 38 to the sub region of tissue
44, the permittivity can be altered within the electric field 36 by
either new elements of the sub region of tissue 44 vibrating in and
out of the electric field such that the continuum permittivity of
the tissue is changed relative to the electric field 36, or that
the bulk properties of the sub region of tissue 44 and the
permittivity, or tissue capacitance, change due to the mechanical
perturbation. An example of altering the permittivity within the
electric field can occur when a cell membrane and extra-cellular
fluid, both of different permittivities, are altered in position
relative to the electric field by the mechanical field. This
movement of tissues of different permittivity relative to the
electric field will generate a new displacement current. The
tissues could have permittivity values as high as or greater than
10^8 times the permittivity of free space, differ by orders of
magnitude, and/or have anisotropic properties such that the tissue
itself demonstrates a different permittivity magnitude depending on
the relative direction of the applied electric field. An example of
altering permittivity of the bulk tissue occurs where the relative
permittivity constant of the bulk tissue is directly altered by
mechanical perturbation in the presence of an electric field. The
mechanical source, i.e., ultrasound source may be placed at any
location relative to the electrode locations, i.e., within or
outside the same location as the electrodes, as long as components
of the electric field and mechanical field are in the same
region.
Tissue permittivities can be altered relative to the applied
electric fields via a number of methods. Mechanical techniques can
be used to either alter the bulk tissue permittivity relative to an
applied electric field or move tissue components of differing
permittivities relative to an applied electric field. There are no
specific limitations to the frequency of the mechanical field that
is applied as previously discussed, however, exemplary frequencies
range from the sub kHZ to 1000s of MHz. A second electromagnetic
field could be applied to the tissue, at a different frequency than
the initial frequency of the applied electromagnetic field, such
that it alters the tissue permittivity at the frequency dependent
point of the initially applied electric field. An optical signal
could also be focused on the tissues to alter the permittivity of
the tissue relative to an applied electric field. A chemical agent
or thermal field could also be applied to the tissues to alter the
permittivity of the tissue relative to an applied electric field.
These methods could also be used in combination to alter the tissue
permittivity relative to an applied electric field via invasive or
noninvasive methods.
For example, FIG. 3 shows a set up 50 for generating an altered
current with a newly generated displacement current 52 through the
combined effects of an electric field 54 and a chemical agent 56. A
tissue or composite of tissues 58 is placed within an electric
source 60 which generates an electric field 54 and combined with
chemical source 62 which releases a chemical agent 56 that can be
focused on the tissue 58. In the area that the chemical agent 56 is
released in the tissue 64, the electric field 54 transects the sub
region of tissue 64, and the chemical agent 56 reacts with the sub
region of tissue 64 to alter the tissue's relative permittivity
relative to the applied electric field 54. This generates a
displacement current 52 in addition to the current that would be
present due to the source electric field 54. The chemical agent 56
may be any agent which can react with the tissue or cellular
components of the tissue 64 to alter its permittivity relative to
the electric field 54. This may be by a thermoreactive process to
raise or lower the tissue 64 temperature or through a chemical
reaction which alters the distribution of ions in the cellular and
extra-cellular media, for instance, along ionic double layers at
cell walls in the tissue 64. Similarly, the conformation of
proteins and other charged components within the tissue 64 could be
altered such that the permittivity of the tissue is altered
relative to the low frequency electric field 54. The agent could
also be any agent that adapts the permanent dipole moments of any
molecules or compounds in the tissue 64, temporarily or permanently
relative to the low frequency electric field 54. The chemical
reaction driven by the chemical agent 56 must work rapidly enough
such that the permittivity of the tissue is quickly altered in the
presence of the electric field 54 in order to generate the
displacement current 52. The reaction may also be such as to
fluctuate the permittivity, such that as the permittivity continues
to change displacement currents continue to be generated. In
addition to the main permittivity change that occurs in the
tissues, a conductivity change could also occur in the tissue,
which secondarily alters the ohmic component of the currents. A
biological agent may be used in place of, or in addition to, the
chemical agent 56. This embodiment may have particular application
for focused drug delivery where an additional chemical or
biological agent is included to assist in therapy of the tissue, or
where the altered current could drive an additional electrochemical
reaction for therapy. For example, this could be used in areas such
as focused gene therapy or focused chemotherapy.
Another example is shown in FIG. 4, which illustrates a set up 70
for applying a method for generating an altered current with a
newly generated displacement current 72 through the combined
effects of a low frequency electric field 74 and an electromagnetic
radiation field 76. A tissue or composite of tissues 78 is placed
within a low frequency electric field 74 which is generated by an
electric source 80 and combined with radiation source 82 which
generates a radiation field 76 that can be focused on the tissue
78. In the area that the radiation field 76 is focused in the
tissue 78, the electric field 74 transects the sub component of
tissue 84, where the radiation field 76 interacts with the sub
component of tissue 84 to alter the tissue's relative permittivity
relative to the applied electric field 74, and as such generates a
displacement current 72 in addition to the current that would be
present due to the source electric field 74 or the radiation source
field 76 alone. The electromagnetic radiation field 76 could, for
example, interact with the tissue 84 by altering its temperature
through ohmic processes, alter the distribution of ions in the
cellular and extra-cellular media for instance along ionic double
layers along cell walls through the electric forces acting on the
ions, or alter the conformation of proteins and other charged
components within the tissue through the electric forces such that
the permittivity of the tissue is altered relative to the low
frequency electric field 74. Furthermore, the electromagnetic field
76, could interact with the tissue 84 by moving components of the
tissue via electrorestrictive forces, as would be seen in
anisotropic tissues, to alter the continuum permittivity of the
tissue relative to the low frequency electric field 74. In addition
to the main permittivity change that occurs in the tissues, a
conductivity change could also occur in the tissue, which
secondarily alters the ohmic component of the currents.
FIG. 5 shows a set up 90 for applying a method for generating an
altered current with a newly generated displacement current 92
through the combined effects of an electric field 94 and an optical
beam 96. A tissue or composite of tissues 98 is placed within
electric field 94 generated by an electric source 100 and combined
with optical source 102 which generates optical beam 96 that can be
focused on the tissue 98. In the area that the optical beam 96 is
focused on the tissue, the electric field 94 transects the sub
component of tissue 104, where the optical beam 96 reacts with the
tissue to alter the tissue's relative permittivity relative to the
applied electric field 94, and as such generates a displacement
current 92 in addition to the current that would be present due to
the source electric field 94. The optical beam 96 could, for
example, interact with the tissue by altering its temperature
through photothermal effects and/or particle excitation, alter the
distribution of ions in the cellular and extra-cellular media for
instance along ionic double layers along cell walls by exciting the
movement of ions optically, ionizing the tissue via laser
tissue-interactions, or alter the conformation of proteins and
other charged components within the tissue such that the
permittivity of the tissue is altered relative to the low frequency
electric field 94. In addition to the main permittivity change that
occurs in the tissues, a conductivity change could also occur in
the tissue, which secondarily alters the ohmic component of the
currents.
In another embodiment, a thermal source to alter the permittivity
of the tissue may be used. In such embodiments, a thermal source
such as a heating probe, a cooling probe, or a hybrid probe may be
placed external or internal to the tissue to be stimulated. A
thermal source may alter the permittivity of the tissue through the
direct permittivity dependence of tissue temperature, mechanical
expansion of tissues in response to temperature changes, or by
mechanical forces that arise due to altered particle and ionic
agitation in response to the temperature alteration such that
permittivity of the tissue is altered relative to an applied
electric field. In addition to the main permittivity change that
occurs in the tissues, a conductivity change could also occur in
the tissue, which secondarily alters the ohmic component of the
currents. This embodiment may be useful for stimulation in the
presence of an acute injury to the tissue where the thermal source
could be used to additionally assist in the treatment of the tissue
injury, for example with a traumatic brain injury or an infarct in
any organ such as the heart. The tissue could be cooled or heated
at the same time stimulation is provided to reduce the impact of an
injury.
In a further embodiment, the method according to the present
disclosure is applied in the area of muscular stimulation, where
amplified, focused, direction altered, and/or attenuated currents
could be used to alter muscular activity via direct stimulation,
depolarizing muscular cells, hyperpolarizing muscular cells,
modifying membrane potentials, and/or increasing or decreasing the
excitability of the muscle cells. This alteration of excitability
or firing patterns can last past the duration of stimulation and
thus be used as a basis to provide lasting treatment. Additionally,
the stimulation can be provided in multiple, but separate sessions
to have a summed, or carry-over effect, on the excitability of
cells and tissue. Additionally, the stimulation could be provided
to prime the tissue by adjusting the muscle cell excitability to
make it more or less susceptible to alternate follow up forms of
stimulation. The stimulation could be used after another form of
stimulation was used to prime the tissue. Furthermore, the
stimulation could be applied for a chronic period of time. This
embodiment may be useful for altering or assisting cardiac pacing
or function, assisted breathing, muscle stimulation for
rehabilitation, muscle stimulation in the presence of nerve or
spinal cord injury to prevent atrophy or assist in movement, or as
substitution for physical exercise.
In yet another embodiment, the method according to the present
disclosure can be applied the area of physical therapy, where
amplified, focused, direction altered, and/or attenuated currents
could be used to stimulate blood flow, increase or alter
neuromuscular response, limit inflammation, speed the break down of
scar tissue, and speed rehabilitation by applying the focus of the
current generation to the effected region in need of physical
therapy. It is envisioned that the method according to the present
disclosure may have a wide variety in the area of physical therapy
including the treatment or rehabilitation of traumatic injuries,
sports injuries, surgical rehabilitation, occupational therapy, and
assisted rehabilitation following neural or muscular injury. For
instance, following an injury to a joint or muscle, there is often
increased inflammation and scar tissue in the region and decreased
neural and muscular response. Typically, ultrasound is provided to
the affected region to increase blood flow to the region and
increase the metabolic re-absorption of the scar tissue while
electrical stimulation is provided separately to the nerves and
muscles; however, by providing them together, a person could
receive the benefit of each individual effect, but additionally
amplified stimulatory and metabolic effects through the altered
currents. The other methods for generating altered currents
discussed within could also be used to assist in physical therapy
via the displacement currents that are generated.
Furthermore, the method according to the present disclosure may be
applied to the area of cellular metabolism, where currents could be
used to interact with electrically receptive cells or charged
membranes to alter the tissue or cellular dynamics. It is
envisioned that this embodiment could provide treatment for various
diseases where electrically receptive cells respond to the newly
generated displacement currents and altered current
distribution.
Furthermore, the method according to the present disclosure may be
applied to the area of gene therapy. Amplified, focused, direction
altered, and/or attenuated currents could be used to interact with
electrically receptive cells or receptors within the cell to
influence protein transcription processes and alter the genetic
content of the cells. The altered current densities in the tissue
can interact with the tissue to stimulate this altered gene
regulation. Additionally, the displacement currents generated by
the method could further be used to assist in drug delivery and/or
gene therapy through the altered current influence on the delivery
of agents.
In certain embodiments, the invention relates to apparatuses and
methods for stimulating and monitoring biological tissue. Any type
of stimulation known in the art may be used with methods of the
invention, and the stimulation may be provided in any clinically
acceptable manner. For example, the stimulation may be provided
invasively or noninvasively. Preferably, the stimulation is
provided in a noninvasive manner. For example, electrodes may be
configured to be applied to the specified tissue, tissues, or
adjacent tissues. As one alternative, the electric source may be
implanted inside the specified tissue, tissues, or adjacent
tissues.
Exemplary types of stimulation include mechanical, optical,
electromagnetic, thermal, or a combination thereof. In particular
embodiments, the stimulation is a mechanical field (i.e., acoustic
field), such as that produced by an ultrasound device. In other
embodiments, the stimulation is an electrical field. In other
embodiments, the stimulation is an magnetic field. Other exemplary
types of stimulation include Transcranial Direct Current
Stimulation (TDCS), Transcranial Ultrasound (TUS)/Transcranial
Doppler Ultrasound (TDUS), Transcranial Electrical Stimulation
(TES), Transcranial Alternating Current Stimulation (TACS), Cranial
Electrical Stimulation (CES), or Transcranial Magnetic Stimulation
(TMS). Other exemplary types include implant methods such as deep
brain stimulation (DBS), microstimulation, spinal cord stimulation
(SCS), and vagal nerve stimulation (VNS). In other embodiments, the
stimulation source may work in part through the alteration of the
nervous tissue electromagnetic properties, where stimulation occurs
from an electric source capable of generating an electric field
across a region of tissue and a means for altering the permittivity
of tissue relative to the electric field, whereby the alteration of
the tissue permittivity relative to the electric field generates a
displacement current in the tissue. The means for altering the
permittivity may include a chemical source, optical source,
mechanical source, thermal source, or electromagnetic source.
In other embodiments, the stimulation is provided by a combination
of an electric field and a mechanical field. The electric field may
be pulsed, time varying, pulsed a plurality of time with each pulse
being for a different length of time, or time invariant. Generally,
the electric source is current that has a frequency from about DC
to approximately 100,000 Hz. The mechanical field may be pulsed,
time varying, or pulsed a plurality of time with each pulse being
for a different length of time. In certain embodiments, the
electric field is a DC electric field.
In other embodiments, the stimulation is a combination of
Transcranial Ultrasound (TUS) and Transcranial Direct Current
Stimulation (TDCS). Such a combination allows for focality (ability
to place stimulation at fixed locations); depth (ability to
selectively reach deep regions of the brain); persistence (ability
to maintain stimulation effect after treatment ends); and
potentiation (ability to stimulate with lower levels of energy than
required by TDCS alone to achieve a clinical effect).
In certain embodiments a medical imaging modality may be combined
with stimulation. Exemplary imaging modalities include magnetic
resonance imaging (MRI), functional MRI (fMRI), ultrasound,
positron emission tomography (PET), single photon emission computed
tomography (SPECT), computer aided tomography scan (CAT-scan),
XRAY, optical coherence tomography (OCT), diffusion tensor imaging
(DTI), diffusion spectrum imaging (DSI), electro-acoustic imaging,
electromagnetic based imaging, electro-encephalogram (EEG),
electromyogram (EMG), high density EEG, spectroscopy based methods,
electrocardiogram (EKG) electrical based imaging, magnetic based
imaging, nuclear based imaging, optical (photonic) based imaging,
mechanical based imaging, thermal based imaging, combined imaging
modalities, imaging with contrast agents, imaging without contrast
agents, etc. In other embodiments, physiological measurements,
stimulation subject assessment measures, and/or biofeedback
measures are combined with stimulation.
The imaging modalities, physiological measurements, stimulation
subject assessment measures, and/or biofeedback measures could be
used to assist in the stimulation by aiding in the targeting
(localizing) of stimulation, dosing of stimulation, characterizing
safety parameters, analyzing the online or offline effects of
stimulation, and/or maximizing the therapeutic effect of
stimulation. This facilitation could also be done by altering or
controlling the stimulation source(s), field parameters, and/or the
stimulation interface apparatus parameters.
In terms of targeting tissues to stimulate, the targeted region can
be imaged with any imaging modality that provides anatomical
information about the region. That image could then be used to
determine the placement of the stimulation source. For example,
with an electrosonic (electrical source and mechanical (i.e.,
sonic/ultrasound), note electrosonic is used synomously with
electromechanical herein) approach one would determine the
placement of the electrical source and the ultrasound source to
target the desired regions, either directly or within an interface
apparatus.
The imaging information could also be used to provide guidance for
the design and property tuning of an interface apparatus between
the subject to be stimulated and the stimulation source(s). For
example, one might simply determine the placement of the source(s)
of stimulation and/or the properties of the interface apparatus
between the stimulation patient and the device (such as for example
the dimensions, materials impedances, and/or design criteria) based
on anatomical landmarks determined from the image and predetermined
source characteristics (such as for example the beam profile of an
ultrasonic transducer and the predicted field distribution of an
electric field source). Further information is described in Wagner
et al. (U.S. patent application number 2010/0070006), the content
of which is incorporated by reference herein in its entirety.
Additionally, the implementation of an imaging system for targeting
could also be used to direct the source fields necessary for
stimulation based on calculations developed from the imaging
information (or to calculate the field to correlate to stimulation
effects following stimulation) and/or physiological measurements,
stimulation subject assessment measures, and/or biofeedback
measures. An imaging modality could be used to identify the tissue
distribution of the subject to be stimulated, from which tissue
boundaries in the stimulation area can be identified. This tissue
and/or boundary identification could be pursued with any image
analysis algorithm, and could be completed prior to stimulation,
during stimulation, or following stimulation.
Once the tissues are identified, a `computational mesh` can be
built to capture the tissue segmentation demonstrated in the
images, where mesh components can be assigned any physical and/or
chemical characteristic of which will be used in determining
targeting and localization of the fields, chemicals, and/or
stimulation effects (e.g., material properties, electromagnetic
properties, thermodynamic properties, mechanical/acoustic
properties, optical properties, chemical properties, etc). These
properties could be assigned known values determined before
stimulation, with values determined during stimulation, or with
values determined following stimulation.
Following the generation of a computational mesh based on the
tissue properties (and geometry) to be modeled, models can be
generated with computational/numerical solvers that capture the
physics and/or chemistry of the underlying system such as by also
including the source and/or interface properties (position, size,
shape, and/or material properties) and/or source field
characteristics (amplitude, waveform (shape/timing dynamics),
frequency (power components and/or pulse frequencies if using
pulsed field), and/or timing information) and/or chemical agent
characteristics (concentrations, distributions, compositions,
kinetics, and/or additional information).
This can be used to determine the driving field's focus,
orientation, focality, and overall distribution in the tissues to
be stimulated (such as for example one could determine the
electrical field, voltage, current density, magnetic field, force
field, mechanical field (acoustic field), pressure field, tissue
acceleration, tissue position, tissue velocity, tissue temperature,
etc) or the chemical reactions and/or chemistry effects that are
modeled (kinetics, chemical distributions, reactions, etc) in the
tissue(s) to be stimulated. For a method where tissue properties
are modified relative to an applied electric field to generate a
new current, this information could then be used to calculate the
altered tissue electromagnetic properties (and/or relative
positions) relative to the applied electrical field in the
tissue(s) to be stimulated, such that one can calculate the newly
generated current density and/or electrical field distributions
(such calculations can be made with any particular means for
altering the tissue electromagnetic properties (including but not
limited to mechanical, thermal, electromagnetic, and optical means)
in the tissue(s) to be stimulated. Additionally, this information
could also be used to guide the placement, design, material
properties, and/or modification of an interface mechanism.
Ultimately this can allow for pre, during, or post stimulation
targeting/localization via calculations based on the initial
imaging modality, tissue characteristics, field source
characteristics, and/or the properties of the interface apparatus
(and/or the source characteristics of the means that alters the
electromagnetic properties of the tissue to be stimulated from
combined methods where new currents are generated relative to an
electric field source). These methods could be implemented with any
form of stimulation, including but not limited to electromagnetic,
mechanical (i.e., acoustic), optical, thermal, electrical,
magnetic, and/or combined methods (and/or methods which alter
tissue impedances relative to electrical sources to generate
altered stimulation currents, for example with electromagnetic,
mechanical (i.e., acoustic), optical, thermal, electrical,
magnetic, and/or combined sources).
In one particular example, in the area of brain stimulation, with
an electrical source generating an applied electrical field and/or
ultrasound (i.e, mechanical) source generating focused acoustic
energy on the tissue area to be stimulated, the electrical field
distribution and/or the mechanical field distribution can be
calculated based on the relative electrical field and mechanical
field transducer source characteristics (transducer position(s),
transducer size(s), transducer shape(s), field frequencies, field
time dynamics, field amplitudes, field phase information, etc) to
anatomical tissue distribution (with the appropriate tissue
characteristics (for example the electromagnetic properties and
tissue mechanical/acoustic properties)) which can be determined
from any imaging methodology which provides anatomical information
about the area to be stimulated (such as for example a CAT-scan or
and MRI) and/or with predetermined tissue characteristics (and/or
also with values which at least in part could be determined via an
imaging modality, such as conductivity characteristics based on DTI
images); for example one might solve a modified Laplacian,
.gradient..differential..times..gradient..PHI..differential..sigma.
.times..PHI. ##EQU00001## for the an electrical potential (where
.PHI. is solved in the sinusoidal steady state for particular
angular frequency, .omega., of the electrical source for particular
permittivities, .di-elect cons., and conductivities, .sigma., of
the tissues being examined (as functions of the frequency of the
stimulation electrical field)) based on a particular electrical
source, and the Westervelt equation:
.gradient..times.
.times..times..differential..times..differential..delta.
.times..times..differential..times..differential..beta..rho..times..times-
..function..times..differential..times..differential..differential..differ-
ential..gradient..gradient..times..times. ##EQU00002##
for a particular mechanical source (where p is pressure, and c is
the speed of sound, .delta. is acoustic diffusivity, .beta. is the
coefficient of nonlinearity, and .rho. is the density of the
respective tissues), and the appropriate boundary conditions
between varied tissues. The calculated electrical and mechanical
field distributions can be used to calculate the altered tissue
electromagnetic properties (and/or relative tissue positions (with
varied tissue electromagnetic properties)) relative to the applied
electrical field, such that one can calculate the newly generated
current density and/or electrical field distributions; for example
one could pursue tissue/field perturbation model and/or a hybrid
Hinch/Fixman (Chew; Fixman 1980; Chew and Sen 1982; Fixman 1982;
Hinch, Sherwood et al. 1983) inspired model of dielectric
enhancement to determine field perturbations and changes in bulk
permittivity, thus ultimately calculating the current density
distributions in the brain during stimulation (where
J=.sigma.E+.differential.(.di-elect cons.E)/.differential.t, J is
the current in the tissue, .sigma. the tissue conductivity, E the
total field (i.e., source plus perturbation field), and .di-elect
cons. is the tissue permittivity; in regions outside of the main
focus fields could be determined through continuity equations).
This information will in turn allow one to predict the distribution
of the fields and/or currents in the brain based on the imaging and
stimulation source information and thus predict locations of effect
of stimulation (and/or magnitude of effect). If one chose to use an
interface apparatus during the stimulation, such as a helmet like
mechanism, the helmet itself could be tailored uniquely for a
subject being stimulated based on the calculated field and/or
targeting information (such as where one could integrate the helmet
design and materials into all of the subsequent physics (and
chemical) based calculations). This information and/or resulting
calculations could also be integrated with physiological
measurements, stimulation subject assessment measures, and/or
biofeedback measures, as it could be used to assist in the
stimulation by aiding in the targeting (localizing) of stimulation,
dosing of stimulation, characterizing safety parameters, and/or
analyzing the online or offline effects of stimulation. This
facilitation can also be done by altering or controlling the
stimulation source(s), field parameters, and/or the stimulation
interface apparatus parameters (based on the calculations and/or
other feedback information).
One could implement a closed loop system which could automatically
tune stimulation based on the calculations and/or feedback which is
gathered and fed into an automated control system(s) to tune
stimulation results to a desired response based on a particular
algorithm and/or an adaptive system; one could implement a system
which allows a person or persons operating the stimulation system
to modify the stimulation system itself to achieve a desired
response relative to the information/feedback that is gathered;
and/or a hybrid system of control (note that the
information/feedback can be gained from any imaging modalities,
biofeedback, physiological measures, and/or other measures as
exemplified above). Accordingly, these methods could be implemented
with any stimulation method by adapting the physical field
calculations appropriately (for example electrical field sources
and effects could be calculated with the modified Laplacian
equation or TUS acoustic fields could be solved with the Westervelt
equation alone (one could also calculate local field changes based
on sources of electrical fields such charged protiens, membranes,
and macromolecules, similar to the methods outlined above).
These methods could be implemented with any form of stimulation.
Exemplary types of stimulation include mechanical, optical,
electromagnetic, thermal, or a combination thereof. In particular
embodiments, the stimulation is a mechanical field (i.e., acoustic
field), such as that produced by an ultrasound device. In other
embodiments, the stimulation is an electrical field. In other
embodiments, the stimulation is a magnetic field. Other exemplary
types of stimulation include Transcranial Direct Current
Stimulation (TDCS), Transcranial Ultrasound (TUS)/Transcranial
Doppler Ultrasound (TDUS), Transcranial Electrical Stimulation
(TES), Transcranial Alternating Current Stimulation (TACS), Cranial
Electrical Stimulation (CES), or Transcranial Magnetic Stimulation
(TMS). Other exemplary types include implant methods such as deep
brain stimulation (DBS), microstimulation, spinal cord stimulation
(SCS), and vagal nerve stimulation (VNS). In other embodiments, the
stimulation source may work in part through the alteration of the
nervous tissue electromagnetic properties, where stimulation occurs
from an electric source capable of generating an electric field
across a region of tissue and a means for altering the permittivity
of tissue relative to the electric field, whereby the alteration of
the tissue permittivity relative to the electric field generates a
displacement current in the tissue. The means for altering the
permittivity may include a chemical source, optical source,
mechanical source, thermal source, or electromagnetic source.
Stimulation targeting, localization, and/or field information could
also be integrated with additional technologies. For instance, one
could integrate the imaging based field solver methodologies with
frameless stereotactic systems to track/target stimulation location
during a procedure. Additionally, as this targeting, localization,
and/or field information can be used to predict the strength and
orientation of the current densities (and/or other fields)
generated in the tissues relative to the tissue to be stimulated,
this information can in turn be fed into neural modeling algorithms
(such as Hodgkin and Huxley based stimulation models) that can be
used to predict the neural response and/or the information can be
used to guide dosing of stimulation. Additionally, the information
could be used to adjust the parameters of stimulation and or the
characteristics of the interface.
Imaging modalities, physiological measurements, stimulation subject
assessment measures, and/or biofeedback measures can also be used
to track the effect of stimulation, and ultimately be integrated
with the stimulator and/or a interface apparatus to provide a
closed loop system of controlled stimulation (and/or with the
targeting/field information described above). Imaging modalities
that provide information such as but not limited to tissue
electrical activity (such as for example, EEG data from the brain
for neural stimulation or EKG information from the heart for
cardiac stimulation or EMG data from muscle during neural and/or
muscle stimulation or electro-retinal gram (ERG) data for visual
system stimulation), tissue metabolic information (such as from
glucose information from a fluorodeoxyglucose (FDG) based PET
scan), tissue blood flow/absorption (such as blood flow information
that might be determined from a BOLD signal that might be
determined during MRI or with modified functional measures),
neuroreceptor activation (such as through radioligands that bind to
dopamine receptors and can be imaged with modalities such as PET),
tissue temperature changes (such as from thermal imaging), and/or
any information of tissue response could be integrated with the
stimulation method to provide system based feedback and provide
guidance to hone stimulation field parameters such as the
stimulation duration, stimulation waveform shape (amplitude and
dynamics); source position, size, shape relative to tissues to be
stimulated; and/or stimulation targeting, localization, and/or
field parameters, such as the source fields timing dynamics,
amplitude and orientation. Such imaging modalities, used to track
the effect of stimulation, could also be integrated with methods
elaborated on above to assist in targeting and dosing
calculations.
Similarly physiological measurements such as but not limited to
heart rate, respiratory rate, blood gas levels, blood pressure,
respiratory gas compositions, urine and fluid concentrations, blood
chemistry (including hormone levels), electrolyte levels, pain
markers, stress indicators, joint function measures (e,g, mobility,
strength, range of motion), patient weight, sensory markers,
auditory measures, perceptual measures, emotional markers, skin
conductance (i.e., sweat level), pupil dilation, emotional markers,
temperature, fluid levels, body/limb position, fatigue markers,
fear markers, coordination measures, psychiatric markers, addiction
markers, motor performance measures, and/or eye position/movement
could be also integrated with the stimulation method to provide
system based feedback and provide guidance to hone stimulation
field parameters such as the stimulation duration, stimulation
waveform shape (amplitude and dynamics); source position, size,
shape relative to tissues to be stimulated; and/or stimulation
targeting, localization, and/or field parameters, such as the
source fields timing dynamics, amplitude and orientation.
Such physiological measurements, used to track the effect of
stimulation, could also be integrated with methods elaborated on
above to assist in targeting and dosing calculations. Additionally,
one could use other biofeedback or stimulation subject assessment
information directly gathered from the subject being stimulated
such as but not limited to task performance (such as a motor
performance, memory, or learning task), subject response (such as
to depression based questionnaire/metrics to assess mood), pain
measures (such as pain assessment levels or amount of pain killers
used), addiction measures (such as alcohol consumption or drug
use), subject gathered reports, subject based observations, and/or
any subject based self assessments could be also integrated with
the stimulation method to provide system based feedback and provide
guidance to hone stimulation field parameters such as the
stimulation duration, stimulation waveform shape (amplitude and
dynamics); source position, size, shape relative to tissues to be
stimulated; and/or stimulation targeting, localization, and/or
field parameters, such as the source fields timing dynamics,
amplitude and orientation. Such measures, used to track the effect
of stimulation, can also be integrated with methods elaborated on
above to assist in targeting and dosing calculations.
One could tune/adjust such things as the stimulation source(s)
position(s), size(s), and/or shape(s) relative to the tissue to be
stimulated (such as the electrodes for generating the electric
fields, transducers for generating acoustic fields, and/or the
source of the means for modifying the electromagnetic parameters of
tissues to be stimulated (i.e., mechanical/acoustic field
source/transducer, optical source, thermal source, chemical source,
and/or a secondary electromagnetic field source)); the field(s)
that are generated from sources in terms of magnitude, direction,
waveform dynamics, frequency characteristics (power spectrum of
waveform and/or potential pulse frequency of stimulation field
waveforms), phase information, and/or the duration of application;
and/or chemical processes (duration, kinetics, chemical
concentrations, distributions, etc) driven by sources.
Additionally, imaging modalities, physiological measures,
biofeedback measures, stimulation subject assessments, and/or other
measures might not just be integrated with the process that
stimulates tissues through the combined application of electrical
and/or mechanical fields (and/or chemical agents, thermal fields,
optical fields/beams, and/or secondary electromagnetic fields), but
effectively they could also be integrated with an interfacing
apparatus to increase the interface apparatus's efficiency or
modify its use relative to the measures outlined above such as but
not limited to altering the material properties of the interface
(such as for example altering the electrical impedance of a
component(s) of the interface or altering a mechanical/acoustic
properties of a component(s) of the interface mechanism such as the
acoustic impendence); alter the interface apparatus position, size,
shape, and/or position; alter the components of the stimulation
process that it stores or interfaces with (such as in size, shape,
and/or position; for example the source of the electric field
and/or means to alter the tissue electromagnetic properties for
tissue stimulation); altering composition(s) of the material(s)
within and/or on the interface (such as fluid concentrations to
couple a mechanical source with tissues to be stimulated); to
control the number of uses of the interface (or the duration of its
use); and/or any adjustable quality as described above in the
interface description.
These modifications can be made before a stimulation session (based
on previously obtained/analyzed information), during stimulation
(with real time or online information), or following stimulation
for subsequent stimulation sessions (with data analyzed following
stimulation). One could also adjust/tune the stimulation parameters
based on the information acquired before stimulation not compared
to anything, during stimulation (online) compared to the
pre-stimulation baseline, inter-stimulation session comparisons,
cross stimulation session comparisons, pre vs. post stimulation
comparisons, across multiple samples (such as across patient
populations with averaged data), and/or any combination or
permutation in which the data is obtained and/or analyzed. These
methods could be implemented with any form of stimulation,
including but not limited to electromagnetic, acoustic, optical,
thermal, electrical, magnetic, and/or combined methods (and/or
methods which alter tissue impedances relative to electrical
sources to generate altered stimulation currents, for example with
electromagnetic, acoustic, optical, thermal, electrical, magnetic,
and/or combined sources).
One could implement a closed loop system which could automatically
tune stimulation based on the information/feedback which is
gathered and fed into an automated control system(s) to tune
stimulation results to a desired response based on a particular
algorithm and/or an adaptive system; one could implement a system
which allows a person or persons operating the stimulation system
to modify the stimulation system itself to achieve a desired
response relative to the information/feedback that is gathered;
and/or a hybrid system of control (note that the
information/feedback can be gained from any imaging modalities,
biofeedback, physiological measures, and/or other measures as
exemplified above).
For example in the area of brain stimulation, with an
electromechanical (i.e., electrosonic) based stimulator, with an
electrical source providing a primary electric field and an
acoustic source providing focused acoustic energy, one could set up
a system such that source electrodes for generating the primary
electric field can have their size, shape, and/or position modified
in real time as directed by imaging information (and/or any other
type of information) that is being gathered during stimulation.
Similarly, one could set up a system such that a source transducer
for generating an acoustic field can have its shape (and/or size)
modified in real time and/or have its position changed in real time
as guided by imaging information (and/or any other type of
information) that is being gathered during stimulation.
Similarly the fields that are generated by these sources can have
their amplitude, waveform dynamics/timing, frequency
characteristics, phase characteristics, distribution, duration,
direction, and/or orientation altered as directed by imaging
information (and/or any other type of information) that is being
gathered before, during, or after stimulation. Similarly if an
interface apparatus is being used, it could have any of
characteristics altered (size, shape, position, material
properties, source contained positions (sizes and/or shapes), etc),
such as for example part of its electrical impedance altered such
that an electrical field that is targeting underlying tissue could
be redirected to another tissue location as guided by imaging
information (and/or any other type of information) that is being
gathered during stimulation. For example, one could provide
electromechanical stimulation (electrical field combined with a
mechanical field) to a subject's brain while simultaneously
recording the EEG response, and subsequently use the EEG imaging
information as a guide to neural response to guide an algorithm
which controls the alteration the electromechanical stimulation
parameters (for example the source position, field amplitudes,
stimulation waveform, stimulation duration, etc) of the electrical
and mechanical field sources to tune the desired EEG response (For
example one could analyze the power and/or frequency information in
the EEG signal relative to stimulation provided, and in turn adjust
the stimulation parameters relative to the EEG signal (such as for
example, the amplitude and/or frequency properties of the
mechanical and electrical source generated fields could be adjusted
relative to the real time EEG response).
Alternatively, for example, one could adjust the location of the
source positions along a stimulation subject's scalp, based on
field calculations made as explained above, but additionally tuned
with functional MRI (fMRI) information depicting location effects
of stimulation, and further integrated with real time EEG data).
The stimulation parameters could simply be modified by a person
administering the stimulation, or be automatically controlled
through a computer/machine based feedback control system during
stimulation (essentially making a closed loop system), and/or a
hybrid system of control. Or furthermore, the interface between the
electrical field source and/or the acoustic field source could be
modified through the controlled feedback system to aid in targeting
or to optimae the therapeutic effect of stimulation.
Additionally, imaging modalities, physiological measures,
biofeedback measures, stimulation subject assessments, and/or other
measures might also be used to monitor safety parameters in the
tissue before, during, and/or after stimulation (either via
calculations based on the imaging and source information, and/or
measured information alone). For instance one could use the thermal
information to assure tissue temperatures remain within desired
levels, electrical activity information to assess for potential
seizure activity or abnormal neural response, current density
magnitude calculations in the tissue (including a breakdown of the
current types (i.e., ohmic vs. capacitive)) to determine if
stimulation currents are within appropriate safety windows,
psychological measures from a stimulation subject response (such as
for example markers for depression and/or mood) to determine if
stimulation is having the appropriate psychological response,
physiological measures from a stimulation subject (such as for
example heart rate and other system measures) to determine if
stimulation parameters are being applied safely, and/or other
various safety markers.
These different methods can all be combined together in whole or in
part and used to tune and/or alter the stimulation source
characteristics, field parameters, calculated fields, the interface
apparatus characteristics, and/or other qualities at any point
before, during, or after stimulation to aid in the targeting
(localizing) of stimulation, dosing of stimulation, characterizing
safety parameters, and/or analyzing the online or offline effects
of stimulation.
Furthermore, such imaging, biofeedback, physiological measurement,
and other modalities in conjunction with the altered current
generation could similarly be applied in the areas of altering
cellular metabolism, physical therapy, drug delivery, and gene
therapy as explained in the referenced patent application (U.S.
patent application Ser. No. 11/764,468, Apparatus and Method for
Stimulation of Biological Tissue) and above as focused on treating
OA. These examples are provided not to be exhaustive, but as an
example of potential applications.
All of the methods, systems, and processes discussed in this
document could be implemented with any form of stimulation,
including but not limited to electromagnetic, acoustic, optical,
thermal, electrical, magnetic, and/or combined methods (and/or
methods which alter tissue impedances relative to electrical
sources to generate altered stimulation currents, for example with
electromagnetic, chemical, acoustic, optical, thermal, electrical,
magnetic, and/or combined sources). Furthermore, all of the
methods, systems, and processes could also be implemented before,
during, and/or after stimulation.
INCORPORATION BY REFERENCE
References and citations to other documents, such as patents,
patent applications, patent publications, journals, books, papers,
web contents, have been made throughout this disclosure. All such
documents are hereby incorporated herein by reference in their
entirety for all purposes.
EQUIVALENTS
The invention may be embodied in other specific forms without
departing from the spirit or essential characteristics thereof. The
foregoing embodiments are therefore to be considered in all
respects illustrative rather than limiting on the invention
described herein.
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